Vine Jacob, Cohen Sara Bar, Ruchlemer Rosa, Goldschmidt Neta, Levin Moshe, Libster Diana, Gural Alexander, Gatt Moshe E, Lavie David, Ben-Yehuda Dina, Rund Deborah
Department of Medicine, Hebrew University-Hadassah Medical School , Jerusalem , Israel.
Leuk Lymphoma. 2014 Nov;55(11):2525-31. doi: 10.3109/10428194.2014.893307. Epub 2014 Mar 19.
The optimal tyrosine kinase inhibitor for any individual patient with chronic myeloid leukemia (CML) is not predictable. Pharmacogenetic parameters and trough levels of imatinib (IM) have each been independently correlated with response. We therefore studied the human organic cation transporter (hOCT1) and multidrug resistance (MDR1) single nucleotide polymorphisms (SNPs) and correlated these with IM levels and major molecular response (MMR) (3-log reduction) in 84 patients with CML, the first such study performed in Caucasians. We studied MDR1 G2677T and C3435T, and for hOCT1, C480G and A1222G. IM levels varied significantly with dose (< or > 400 mg/day) (p = 0.038) and were significantly lower in 20 patients who lost MMR (p = 0.042). Adjusting for dose, trough IM levels were not significantly correlated with SNPs. Patients with MDR1 3435 TT had significantly longer times to MMR compared to CC/CT genotypes (p = 0.047). Genotypes did not predict treatment failure when controlling for IM levels. We conclude that IM levels, but not the SNPs studied here, determine IM failure.
对于任何一位慢性髓性白血病（CML）患者而言，最佳的酪氨酸激酶抑制剂是无法预测的。伊马替尼（IM）的药物遗传学参数和谷浓度均各自独立地与反应相关。因此，我们研究了人类有机阳离子转运体（hOCT1）和多药耐药性（MDR1）单核苷酸多态性（SNP），并将其与84例CML患者的IM水平和主要分子反应（MMR，3-log降低）进行关联分析，这是在白种人中开展的首例此类研究。我们研究了MDR1的G2677T和C3435T，以及hOCT1的C480G和A1222G。IM水平随剂量（<或>400 mg/天）有显著变化（p = 0.038），并且在20例失去MMR的患者中显著更低（p = 0.042）。校正剂量后，IM谷浓度与SNP无显著相关性。与CC/CT基因型相比，MDR1 3435 TT基因型的患者达到MMR的时间显著更长（p = 0.047）。在控制IM水平时，基因型无法预测治疗失败。我们得出结论，决定IM治疗失败的是IM水平，而非此处研究的SNP。
